Bladder cancer (BCa) is among the five most common malignancies worldwide. In the US alone, new BCa cases for 2012 are estimated at 73,500 with estimated deaths at 14,880. At presentation, the majority of bladder tumors are non?muscle invasive, and can be treated by transurethral resection of the tumor, however, more than 70% of patients with BCa will have a recurrence during the first two years after diagnosis. This recurrence phenomenon makes BCa one of the most prevalent cancers worldwide. Furthermore, once treated, patients are under continued surveillance with routine cystoscopy for detection of new tumor development, so the healthcare costs of BCa are a major burden. The overall goal of this project is to develop assays that can achieve the accurate, non?invasive detection of BCa via urinalysis. Using high?throughput genomic profiling technologies, we have derived a series of molecular signatures that outperform any currently used urinalysis assay for BCa detection. The first specific aims are designed to validate the diagnostic accuracy of components of these signatures using alternative techniques. The goal is to establish the technical and scientific merit of the approach. Further specific aims will be designed to determine the feasibility of developing selected nucleic acid?based molecular signatures into robust assays with clinical utility. At the end of the proposed study, assays will be ready for development for use in the clinic. The development of non?invasive, urine based assays for bladder cancer detection and disease status evaluation will be of tremendous benefit to both patients and the healthcare system.